The proposed research involves the characterization of atherosclerotic plaque through the synthesis and evaluation of molecularly targeted contrast agents to be imaged using a combined intravascular ultrasound and photoacoustic (IVUS/IVPA) imaging modality. Despite improved understanding of the biological progression of plaques which are vulnerable to rupture and cause acute coronary events, clinical imaging modalities fail to provide corresponding compositional information necessary to improve patient diagnosis. Through the combination of ultrasound and photoacoustics, IVUS/IVPA imaging provides unique advantages to diagnosing plaque composition in that it is capable of imaging the entire thickness of the arterial wall with optical contrast. The proposed research will demonstrate contrast-enhanced IVUS/IVPA imaging of atherosclerosis. The underlying hypothesis is that IVUS/IVPA imaging of molecularly targeted contrast agents will provide the ability to image biomarkers of plaque instability, specifically v3 integrins, with high sensitivity and resolution while imaging through arterial blood. The first aim of the project is to synthesize plasmonic nanoparticle contrast agents conjugated with vulnerable plaque targeting moieties (e.g., RGD peptides). The second aim is to demonstrate in vitro, receptor-specific targeting of the bioconjugated contrast agents. Endocytosis of the targeted plasmonic nanoparticles by cells expressing the appropriate receptor will be assessed using optical and photoacoustic imaging techniques. IVUS/IVPA imaging of tissue-mimicking phantoms containing inclusions with contrast agent-loaded cells will be conducted to confirm contrast enhancement and develop strategies for distinguishing the exogenous contrast agents from endogenous chromophores. The third aim will demonstrate ex vivo IVUS/IVPA imaging of molecular-targeted contrast agents systemically injected into rabbit models of atherosclerosis. In order to accomplish these goals, the proposed training plan is designed to ensure interaction of trainee mentors with relevant technical experience. The selected mentors have expertise in the synthesis and applications of plasmonic nanoparticles for biomedical applications as well as in ultrasound and photoacoustic imaging. The trainee will undergo formal training in research-relevant topics and ethical conduct of research to further facilitate accomplishment of the proposed project.